Interplay of the inflammatory and stress systems in a hepatic cell line : interactions between glucocorticoid receptor agonists and interleukin-6

Visser, Koch ; Smith, Carine ; Louw, Ann (2010-11)

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The liver plays an important role in inflammation and stress by producing the acute phase proteins (APPs) required for resolution of inflammation as well as by delivering systemic glucose, through gluconeogenesis, required to fuel the stress response. Disruption of the interplay between interleukin 6 (IL-6) and glucocorticoids (GCs), the peripheral mediators of inflammation and stress, respectively, maylead to side-effects associated with the pharmacological use of GCs.Thecurrent study investigated the interplay between IL-6 and GCs in a hepatoma cell line (BWTG3) at protein (protein activity assays, Western blotting, and ELISA) andmRNA(qPCR) levels. Specifically, the action of dexamethasone (Dex), a known antiinflammatory drug and glucocorticoid receptor (GR) agonist, is compared to that of Compound A (CpdA), a selective glucocorticoid receptor agonist (SEGRA). CpdA, like IL-6, but unlike Dex, increases GR binding and decreases the metabolic enzymes, tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, andgammaglutamyltransferase, at protein ormRNAlevel. Like Dex, both CpdA and IL-6 increase the positive APPs, serum amyloid A and C-reactive protein, and decrease the negative APP, corticosteroid binding globulin. The study shows that the GC, Dex, and IL-6 generally have divergent effects on the GR and metabolic enzymes, while their functions are convergent on the APPs. In contrast to Dex,CpdAhas effects convergent to that of IL-6onthe GR, metabolic enzymes,and APPs. Thus these findings suggest that CpdA, like Dex, modulates APPs, leading to effective control of inflammation, while, in contrast to Dex, it is less likely to lead to GC-induced side-effects.

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